The treatment of Human Immunodeficiency Virus (HIV) infection, generally recognized as cause of the acquired immunodeficiency syndrome (AIDS), remains a major medical challenge. Currently available HIV inhibitors include nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), HIV-protease inhibitors (PIs), fusion inhibitors, and the more recent CCR5 and integrase inhibitors.
Current standard of care is based on combination therapy of several anti-HIV agents of a different activity profile. One class of HIV drugs used in combinations is that of the NNRTIs, a number of which are currently on the market while others are in various stages of development. An NNRTI that is on the market is the compound 4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile, also referred to as etravirine or as TMC125. In a growing number of countries, etravirine is on the market under the tradename “Intelence™”. This compound not only shows pronounced activity against wild type HIV, but also against many mutated HIV strains. Etravirine, its pharmacological activity, as well as a number of procedures for its preparation have been described in WO 00/27825.
Etravirine is very insoluble in aqueous media and therefore suffers from very low bioavailability. Traditional formulations resulted in no or very low blood plasma levels. WO 01/23362 and WO 01/22938 disclose solid dispersions of this compound in water-soluble polymers offering improved bioavailability, especially when in the form of powders prepared by spray-drying. Intelence™ is available as tablets that contain a solid dispersion of TMC125 in HPMC obtained by spray-drying. The current dosing regimen of etravirine is 200 mg twice a day (b.i.d.), administered as two tablets each containing 100 mg, to be taken in at once, preferably two in the morning and two at the end of the day. Because of these dosing requirements and the fact that etravirine is dispersed in a relatively large quantity of water-soluble polymer, dosage forms of this drug inevitably are large in size. This contributes to the so-called “pill-burden”, a term that covers all inconveniences associated with the intake of drugs such as, for example, frequent daily dosing, specific administration requirements, e.g. before, during or after a meal, large dosage forms, or combinations of these factors. Large dosage forms can be problematic for patients having difficulty in swallowing, such as children or the elderly. Frequent dosing and specific administration requirements put a heavy burden on patients not to forget taking their medication and to take it at the right time. All these factors contribute to the risk that patients will not take their entire dose, thereby failing to comply with the prescribed dosage regimen. As well as reducing the effectiveness of the treatment, this may also lead to the virus becoming resistant to the drug that is administered. The problems associated with a high pill burden are multiplied where a patient must take a combination of a number of different types of pharmaceutical agents such as in anti-HIV therapy.
One way to improve the bioavailability of poorly soluble active agents is by converting them into the amorphous form. Typically, the higher the degree of crystallinity of the pharmaceutical agent, the lower is its bioavailability. Amorphous forms, however, are difficult to prepare and quickly convert to the thermodynamically more stable crystalline form. They can be stabilized by incorporation in a solid dispersion matrix, which in the case of pharmaceuticals typically is a water-soluble polymer. This results in large volume dosage forms since a relatively large amount of matrix material is required to obtain a stable solid dispersion
The crystalline state of drug substances is preferred because of the relative ease of isolation, the removal of impurities during the crystallization process, and the physicochemical stability that the crystalline solid state generally affords. These advantages are often counter-balanced by disadvantageous features of the crystalline state, such as poor solubility, hygroscopicity, dissolution rate, and other associated performance characteristics.
The provision of drug substances in co-crystalline forms can offer an alternative approach to modify or control the physicochemical properties of a drug substance. It can offer an alternative to the conversion into the amorphous state with its associated problems or to the conversion into salt forms, which in a number of instances do not offer the desired physicochemical properties. Co-crystallization can also be used to isolate or purify a drug substance during manufacturing.
Pharmaceutical co-crystals are crystalline molecular complexes that contain the drug substance along with an additional molecule present in the same crystal structure. The additional molecule or guest has been described in the literature as a co-crystal former. A co-crystal can thus be seen to be a multiple component crystal in which the drug substance and the co-crystal former are arranged in a three dimensional repetitive structure, wherein non-covalent and non-ion pair interactions exist between the drug substance and the co-crystal former, such as hydrogen bonding, pi-stacking, and van der Waals interactions. Co-crystalline forms show different physicochemical properties compared to the drug substance alone, including melting point, chemical reactivity, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density. These properties can have a direct effect on the ability to process and/or manufacture a drug substance and the corresponding finalized dosage forms, as well as an effect on drug product stability, dissolution, and bioavailability. Thus co-crystallization can affect the quality, safety, and efficacy of a drug substance.
Co-crystal formation and the properties of co-crystalline forms cannot be predicted on the basis of known properties of the drug substance and the co-crystal former.
Co-crystalline forms of a drug substance can be characterized by a number of methods including, for example, X-ray powder diffraction, microscopy, thermal analysis (e.g. differential scanning calorimetry, thermal gravimetric analysis and hot-stage microscopy), spectroscopy (e.g., infrared (IR) and near infrared (NIR), Raman, solid-state nuclear magnetic resonance (ssNMR)), and in particular by single crystal X-ray diffraction.
It now has been found that etravirine and nicotinamide form a co-crystal that demonstrates improved properties as compared to etravirine alone. This co-crystal shows an improved dissolution profile of etravirine in in-vitro experiments. In particular the dissolution rate in aqueous media (simulated gastric fluid) of the etravirine active ingredient from a solid dispersion is increased and prolonged, resulting in higher concentrations of the drug. This may result into higher plasma levels and a quicker onset of the etravirine active ingredient. This allows for more compact dosage forms, which in turn helps to overcome problems associated with pill burden.